Duloxetine HCl is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI), depression, and pain management. It is commercially available as CYMBALTA®. Duloxetine hydrochloride has the chemical name (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloric acid salt and the following structure.

Duloxetine, as well as processes for its preparation, is disclosed in a few published documents, such as U.S. Pat. No. 5,023,269, EP Patent No. 457559 and U.S. Pat. No. 6,541,668.
The conversion of duloxetine to its hydrochloride salt is described in U.S. Pat. No. 5,491,243 and in Wheeler W. J., et al, J. Label. Cpds.Radiopharm, 1995, 36, 312. In both cases the reactions are performed in ethyl acetate.
Like any synthetic compound, duloxetine HCl can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in duloxetine HCl or any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient being treated with a dosage form of the API in which a sufficient amount of impurities is present. Furthermore, the undesired enantiomeric impurities reduce the level of the API available in the pharmaceutical composition.
It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of an API, such as duloxetine hydrochloride, it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Generally, side products, by-products, and adjunct reagents (collectively “impurities”) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W. R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley & Sons: New York 1989)).
(+)-N-methyl-3-(1-naphthalenyloxy)-3-(3-thienyl)propanamine is disclosed by Olsen B. A et al, as an impurity obtained in the preparation of duloxetine (J. Lib. Chrom. & Rel. Technol, 1996, 19, 1993).
There is a need in the art for a process for preparing chemically and/or enantiomerically pure duloxetine HCl